Ultrasonic surgical instrument for intracorporeal sonodynamic therapy

ABSTRACT

The present invention relates, in general, to ultrasonic surgical instruments and, more particularly, to an intracorporeal ultrasonic surgical instrument for sonodynamic therapy. Disclosed is an ultrasonic surgical system comprising: a generator and an instrument comprising: a housing; a transducer; a semi-permeable membrane; a pharmaceutical agent; and an agent delivery system. The transducer is adapted to convert the electrical energy of the generator into mechanical energy. The pharmaceutical agent, delivered into a chamber of the semi-permeable membrane, is driven through the semi-permeable membrane by the mechanical energy. A method in accordance with the present invention comprises the steps of: providing a surgical instrument comprising: a housing; a transducer connected to the housing; a semi-permeable membrane; a pharmaceutical agent; and an agent delivery system; inserting the surgical instrument into a patient; delivering a drug to the patient; and locally activating the drug with the surgical instrument.

CROSS REFERENCE TO RELATED PATENT INFORMATION

This application is related to, and claims the benefit of, U.S.provisional patent application Ser. No. 60/302,070 filed Jun. 29, 2001,which is hereby incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates, in general, to ultrasonic surgicalinstruments and, more particularly, to an ultrasonic surgical instrumentfor intracorporeal sonodynamic therapy.

BACKGROUND OF THE INVENTION

Ultrasonic instruments, including both hollow core and solid coreinstruments, are used for the safe and effective treatment of manymedical conditions. Ultrasonic instruments, and particularly solid coreultrasonic instruments, are advantageous because they may be used to cutand/or coagulate organic tissue using energy in the form of mechanicalvibrations transmitted to a surgical end-effector at ultrasonicfrequencies. Ultrasonic vibrations, when transmitted to organic tissueat suitable energy levels and using a suitable end-effector, may be usedto cut, dissect, or cauterize tissue. Ultrasonic instruments utilizingsolid core technology are particularly advantageous because of theamount of ultrasonic energy that may be transmitted from the ultrasonictransducer through the waveguide to the surgical end-effector. Suchinstruments are particularly suited for use in minimally invasiveprocedures, such as endoscopic or laparoscopic procedures, wherein theend-effector is passed through a trocar to reach the surgical site.

Ultrasonic vibration is induced in the surgical end-effector by, forexample, electrically exciting an electromechanical element, which maybe constructed of one or more piezoelectric or magnetostrictive elementsin the instrument handpiece. Vibrations generated by theelectromechanical element are transmitted to the surgical end-effectorvia an ultrasonic waveguide extending from the transducer section to thesurgical end-effector.

Another form of ultrasonic surgery is performed by High IntensityFocused Ultrasound, commonly referred to as “HIFU”. HIFU is currentlyused for lithotripsy procedures where kidney stones are broken up intosmall pieces by ultrasonic shock waves generated through ultrasoundenergy focussed into the body from an extracorporeal source. HIFU isalso under investigational use for treating ailments such as benignprostatic hyperplasia, uterine fibroids, liver lesions, and prostatecancer.

Examples of uses of ultrasound to treat the body can be found in U.S.Pat. Nos. 4,767,402; 4,821,740; 5,016,615; 6,113,570; 6,113,558;6,002,961; 6,176,842 B1; PCT International Publication numbers WO00/27293; WO 98/00194; WO 97/04832; WO 00/48518; WO 00/38580; WO98/48711; and Russian Patent number RU 2152773 C1.

Although the aforementioned devices and methods have proven successful,it would be advantageous to provide an intracorporeal instrument forsonodynamic therapy, and methods of sonodynamic treatment capable ofimproved outcomes for patients. This invention provides such anintracorporeal instrumennt and method for sonodynamic therapy.

SUMMARY OF THE INVENTION

The present invention relates, in general, to ultrasonic surgicalinstruments and, more particularly, to an ultrasonic surgical instrumentfor intracorporeal sonodynamic therapy. Specifically, the inventionrelates to an intracorporeal surgical instrument capable ofenhanced/controlled delivery and activation of pharmaceutical agents aswell as to achieve tissue ablation. Representative pharmaceutical agentsinclude analgesics, anti-inflammatories, anti-cancer agents,bacteriostatics, neuro active agents, anticoagulants, high-molecularweight proteins, for example, for gene delivery, among others. Theinstrument is designed to operate in the kHz and/or MHz frequencyranges.

Disclosed is an ultrasonic surgical system comprising a generator and aninstrument comprising a housing; a transducer connected to the housing;a depot for chemicals including a semi-permeable membrane,bio-degradable packet, drug impregnated depots and liposomes amongothers; a pharmaceutical agent; and an agent delivery system. Thegenerator is adapted to provide electrical energy to the transducer. Thetransducer is adapted to convert the electrical energy into mechanicalenergy. The agent delivery system delivers the pharmaceutical agent intoa chamber of the semi-permeable membrane; and the pharmaceutical agentis driven through the semi-permeable membrane by the mechanical energy.Advantageously, the transducer may be combined with other surgicalinstruments such as ultrasound, iopntophoretic, laser, electrosurgical,for example RF, and eletroporative devices to achieve tissue ablation aswell as the sonodynamic therapy.

The present invention has application in endoscopic and conventionalopen-surgical instrumentation as well as application in robotic-assistedsurgery.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. The invention itself, however, both as toorganization and methods of operation, together with further objects andadvantages thereof, may best be understood by reference to the followingdescription, taken in conjunction with the accompanying drawings inwhich:

FIG. 1 is a perspective view of an ultrasonic system in accordance withthe present invention;

FIG. 2 is a perspective view of an alternate agent injection device foran ultrasonic instrument in accordance with the present invention;

FIG. 3 is a perspective view of an ultrasonic surgical end-effector ofan ultrasonic system in accordance with the present invention;

FIG. 4 is a sectioned view of a portion of an intense ultrasoundinstrument in accordance with the present invention;

FIG. 5 is a perspective view of an alternate embodiment of an ultrasonicsystem in accordance with the present invention;

FIG. 6 is a perspective view of an alternate agent injection device foran alternate embodiment of an ultrasonic instrument in accordance withthe present invention;

FIG. 7 is a perspective view of an ultrasonic surgical instrumentend-effector of an ultrasonic system in accordance with the presentinvention;

FIG. 8 is a sectioned view of a portion of an ultrasonic surgicalinstrument in accordance with the present invention;

FIG. 9 is a sectioned view of a portion of an ultrasonic surgicalinstrument in accordance with the present invention;

FIG. 10 is a perspective view of an alternate embodiment of anultrasonic system in accordance with the present invention;

FIG. 11 is a graph illustrating the transport of an agent with andwithout ultrasound energy;

FIG. 12 is a graph of the response characteristics of a transducer inaccordance with the invention of FIGS. 1-4; and

FIG. 13 is a plot of the calculated acoustic intensities of thetransducer in accordance with the invention of FIGS. 1-4.

DETAILED DESCRIPTION OF THE INVENTION

Before explaining the present invention in detail, it should be notedthat the invention is not limited in its application or use to thedetails of construction and arrangement of parts illustrated in theaccompanying drawings and description. The illustrative embodiments ofthe invention may be implemented or incorporated in other embodiments,variations and modifications, and may be practiced or carried out invarious ways. Furthermore, unless otherwise indicated, the terms andexpressions employed herein have been chosen for the purpose ofdescribing the illustrative embodiments of the present invention for theconvenience of the reader and are not for the purpose of limiting theinvention.

It is well known to those skilled in the art that ultrasound operatingat kHz frequencies can reversibly change the permeability of cellbarriers and/or activate drugs. Most of the work in this area describesthe drug delivery applications through the skin, or enhancement ofthrombolytic activity in the blood vessels. An approach where a surgeonperforms an excision using an ultrasonic surgical instrument, and then“delivers” a chemotherapeutic agent in the treatment field would improvethe treatment outcomes.

The attenuation coefficient for sound at kHz frequencies in tissue isvery low, even assuming a radial spread of acoustic energy from the endeffector. There is sufficient energy distal from the end effector, froma few millimeters to a couple of centimeters, such that the permeabilityof cells can be affected. Two examples, which are not intended to limitthe scope of the invention, of intracorporeal drug delivery/enhancementare enabled by the present invention. One, local drug delivery in theregion of surgical treatment as described earlier. Second, thetherapeutic chemical agent is given intravenously, and the drug isactivated in a region of interest during an interventional procedureusing laparoscopic kHz and/or MHz frequency ultrasound.

For management of cancers, intra-operative delivery of chemotherapeuticagents and treatment with ultrasound energy is provided by the presentinvention to increase the efficacy of surgery and reduce recurrencerates, as well as to reduce the risk of seeding healthy sites withcancerous cells during intervention. Such local and site specific drugdelivery approaches with kHz and/or MHz frequency ultrasound could beapplied in surgical procedures, such as, for example, liver, colon,prostate, lung, kidney, and breast. A surgical patient may furtherbenefit from the increase in treatment volume that may result from achemical agent used in cooperation with kHz and/or MHz ultrasonic energyas well as from chemical agents used with the present invention thatwould otherwise be adversely affected if used with other forms ofenergy. In general, the chemical agents whose efficacy can be enhancedwith the present invention may be chemotoxic drugs such as, for example,Paclitaxel, Docetaxel, trademark names of Bristol Meyers-Squibb orantibiotics, bacteriostatics, or cholinesterase inhibitors such asGalantamine, trademark name Reminyl of Johnson and Johnson, that may bedelivered locally before completion of a surgical procedure. Chemicalagents whose efficacy may be enhanced with the present invention furtherinclude local anesthetics such as, but not limited to, Novacaine,anti-inflammatories, corticosteroids, or opiate analgesics.

FIG. 1 illustrates an ultrasonic system 25 for local delivery of anagent in combination with an intense ultrasound instrument 50 foractivating or assisting transport of the agent. Intense ultrasoundinstrument 50 includes an elongated portion 68, a housing 74, a grip 69,a porous or semi-permeable membrane 55, and a port 79. An agent 75 iscontained in a container 76 for insertion into port 79. Insertion ofcontainer 76 into port 79 may be done mechanically, or manually by theoperator. Intense ultrasound instrument 50 includes a radiatingend-effector 60. Intense ultrasound instrument 50 is connectable to agenerator 10 via cable 90, that supplies electrical energy to radiatingend-effector 60 for conversion by transducer 65 to ultrasonic stresswaves. Radiating end-effector 60 comprises a plurality of embodimentsincluding, but not limited to, single element, array-based endeffectors, planar transducers, shaped transducers, or end effectors withactive-passive element combinations.

A foot switch 95 is connected to generator 10 via cable 98 to controlgenerator 10 function. A switch 96 and a switch 97 are included withfoot switch 95 to control multiple functions. For example, switch 96could provide a first level of energy to radiate end-effector 60 and aswitch 97 could provide a second level of energy to radiate end-effector60. Generator 10 may also include a display 80 for providing informationto the user, and buttons or switches 81, 82, and 83 to allow user inputinto the generator such as, for example, turning the power on, settinglevels, defining device attributes or the like.

FIG. 2 illustrates an alternate means of providing agent 75 to intenseultrasound instrument 50. In this embodiment, a syringe 77 containsagent 75 for injection to a surgical site within a patient. A plunger 73may be depressed by the operator to deliver agent 75 to a surgical sitevia port 78.

FIG. 3 illustrates a method of using an instrument in accordance withthe present invention. End-effector 60 is inserted into the body cavityof a patient, and located on or near tissue 40 that includes a spot orlesion 45 for treatment with agent 75. Spot or lesion 45 may be acancerous region, a polyp, or other area that would benefit fromtreatment with agent 75. Semi-permeable membrane 55 contains agent 75under instrument-off conditions, once agent 75 has been delivered tosemi-permeable membrane 55. Agent 75 may be delivered to semi-permeablemembrane 55 by way of an agent channel 63 (FIG. 4). An alternateembodiment of intense ultrasound instrument 50 contemplates thedisposable use of intense ultrasound instrument 50 where semi-permeablemembrane 55 is manufactured containing a pre-selected agent 75 locatedwithin semi-permeable membrane 55. The single use embodiment of intenseultrasound instrument 50 comprises disposal of intense ultrasoundinstrument 50, semi-permeable membrane 55, and/or end effector 60.Alternatively, and not by way of limitation of the invention, membrane55 could take the form of a biocompatible biodegradable layer that isimpregnated with a therapeutic chemical agent with or without thepresence of cavitation nuclei. The therapeutic agent may bepreferentially delivered at the target site when the ultrasoundinstrument 50 is energized.

When intense ultrasound instrument 50 is activated, agent 75 is driventhrough semi-permeable membrane 55, producing agent droplets 77. Asuitable semi-permeable membrane 55 may be formed from, for example,nitrocellulose, tyvek, silicone, ethelyne vinyl acetate, or the like.Semi-permeable membrane 55 may be semi-permeable in specific regions andmay be non-permeable in other regions to effectuate targeted release ofthe agent 75 through membrane 55. Further, semi-permeable membrane 55may be bio-compatible and have a tissue adhesive, allowing for thesemi-permeable membrane 55 to be left within a body cavity, and/or maybe adapted to dissolve within a body cavity. Agent droplets 77 aredriven preferentially into tissue 40 by ultrasound energy, as shownbelow in ultrasound-mediated diffusion experiment results.

Intense ultrasound instrument 50 may further comprise the use of asuction system, an irrigation system, a snare, a viewing means, acoolant means, an imaging means, a biopsy system, a gene delivery means,and/or a number of cutting and/or coagulation means such as, forexample, laser, iontophoretics, electroporative devices, orelectrosurgical energy. The present invention further comprises theseeding of tissue 40 to facilitate enhanced ablation and/or agentdroplet 77 delivery such as the introduction of foreign particles, theintroduction of stabilized microbubbles, aeration, and/or a pulseprofile designed to meet the needs of a particular medical application.

Agent 75 is injectable into chamber 57 of semi-permeable membrane 55through port 62 under pressure from syringe 77, container 76, or byother suitable means of delivery. Agent 75 may be Vorozole, Paclitaxel,Docetaxel, bacteriostatics, antibiotics, anti-coagulants, glues, genes,chemotoxic agents, or any other agent having properties beneficial tothe outcomes of the medical treatment or surgical procedure. Chemicalagents whose efficacy may be enhanced with the present invention furtherinclude local anesthetics such as, but not limited to, Novacaine,anti-inflammatories, corticosteroids, or opiate analgesics.

FIG. 4 illustrates a section of elongated portion 68. Residing insideelongated portion 68 is an agent channel 63, a coaxial cable 66, and alead 64. Agent channel 63 delivers the agent 75 from the proximal end ofintense ultrasound instrument 50 to the radiating end-effector 60 viaport 62. Coaxial cable 66 delivers electrical energy to transducer 65.In one embodiment, when electrically activated, transducer 65 operatespreferably at 0.5-50 MHz, and more preferably at 0.5-10 MHz, and morepreferably at 0.5-2 MHz. Lead 64 may be used to transmit a feedbacksignal from the radiating end-effector 60 to generator 10 such as, forexample, temperature information from a thermocouple, acoustic noiselevel from a hydrophone, or the like. The present invention furthercontemplates the use of a plurality of coaxial cables 66, leads 64,and/or agent channels 63. Coaxial cable 66 may be designed from anyconductive material suitable for use in surgical procedures. In oneembodiment of the present invention, agent channel 63 comprises at leastone lumen constructed from plastic, metal, rubber, or other materialsuitable for use in surgical procedures.

A design representative of an intra-corporeal MHz-frequency ablation andSonodynamic therapy prototype may be, for example, a UTX Model #0008015(UTX, Inc., Holmes, N.Y.). This may be designed around a 20 cm long tubethat fits through a 5 mm trocar. At the distal end of this tube, thereis one spherically curved ceramic element (4×15 mm, radius ofcurvature=25 mm). The transducer design accomplishes narrow bandwidthoperation around 2 MHz. (as shown in FIG. 12). The acoustic output atsource may be ˜20 W/cm². The acoustic intensity around the focal zonemay be on the order of 200 W/cm², (FIG. 13), sufficient to cause tissueablation in the treatment volume. In addition, there is sufficientacoustic energy range available for accomplishing enhanced drug-deliveryor drug activation steps.

As is known in the art, the connecting cable 90 may be shielded coax. Ifneeded, there may be an additional electrical matching network betweenthe power amplifier and the transducer. The front faces of thetransducer active surfaces have acoustic matching layers. Thetransducers are “air-backed.” Thin, 0.125 mm, diameter thermocouples maybe attached close to the ceramic faces that help monitor any selfheating of the ultrasonic sources. Membrane 55 may be silicone,polyurethane, or polyester-based balloons to ensure that most of theenergy radiated by the transducer is delivered to the tissue and notreflected back from the source tissue interface.

A further embodiment of ultrasonic system 25 comprises the systemicdelivery of agent 75 in cooperation with intense ultrasound instrument50. Agent 75 may be ingested, injected or systemically delivered byother suitable means. Intense ultrasound instrument 50 may then beactivated on or near tissue 40 where the effects of intense ultrasoundare desired.

FIG. 5 illustrates an ultrasonic system 125 for local delivery of anagent 175 in combination with an ultrasonic surgical instrument 150 foractivating or assisting transport of the agent 175. Ultrasonic surgicalinstrument 150 includes an elongated portion 168, a housing 174, anelectro-mechanical element 165, for example, a piezoelectric transducerstack, a grip 169, a semi-permeable membrane 155, and a port 179. Anagent 175 is contained in a container 176. Container 176 is insertableinto port 179 of a housing 174. Alternatively, agent 175 may bedelivered via a syringe 177 through a port 178 as shown in FIG. 6.Ultrasonic surgical instrument 150 includes a contact end-effector 160.Ultrasonic surgical instrument 150 is connectable to a generator 200 viacable 190, that supplies electrical energy to a transducer 165 thatdelivers stress waves to contact end-effector 160 via a waveguide 146(FIG. 8). In one embodiment, when electrically active, electromechanicalelement 165 operates preferably at 10-200 kHz, more preferably and morepreferably at 10-75 kHz. A clamp arm 170 may be attached to elongatedportion 168, to provide compression of tissue 145 (FIG. 7) between clamparm 170 and a blade 147 at the distal end of waveguide 146. Blade 147comprises a plurality of embodiments including, but not limited to, acurved form, a straight form, a ball form, a hook form, a short form, along form, or a wide form.

Referring now to FIG. 7 end-effector 160 may be inserted into the bodycavity of a patient, and located on or near tissue 140 that includes aspot or lesion 145 for treatment with agent 175. Spot or lesion 145 maybe a cancerous region, a polyp, or other area that would benefit fromtreatment with agent 175. Semi-permeable membrane 155 contains agent 175under instrument-off conditions once agent 175 has been delivered tosemi-permeable membrane 155. Agent 175 may be delivered tosemi-permeable membrane 155 by way of an agent channel 163 (FIG. 8). Analternate embodiment of ultrasonic surgical instrument 150 comprises thesingle use of ultrasonic sugical instrument 150 where semi-permeablemembrane 155 may be manufactured containing a pre-selected agent 175located within semi-permeable membrane 155. The single use embodiment ofultrasonic surgical instrument 150 further contemplates disposal ofultrasonic surgical instrument 150, semi-permeable membrane 155, and/orend effector 160. When ultrasonic surgical instrument 150 is activated,agent 175 is driven through semi-permeable membrane 155, producing agentdroplets 177. A suitable semi-permeable membrane 155 may be formed from,for example, nitrocellulose, tyvek, silicone, ethelyne vinyl acetate, orthe like. Agent droplets 177 are then driven preferentially into tissue140 by ultrasound energy, as shown below in ultrasound-mediateddiffusion experiment results. Ultrasonic surgical instrument 150 furthercontemplates the use of a suction system, an irrigation system, a snare,a viewing means, and/or a number of cutting and/or coagulation meanssuch as, for example, laser, iontophoretics, electroporative devices, orelectrosurgical energy.

FIG. 8 illustrates a section of elongated portion 168. Residing insideelongated portion 168 may be an agent channel 163, solid waveguide 146,and a lead 164. Agent channel 163 delivers the agent 175 from theproximal end of ultrasonic surgical instrument 150 to the contactend-effector 160. Lead 164 may be used to transmit a signal from theradiating end-effector 160 to generator 200 such as, for example,temperature information from a thermocouple, acoustic noise level from ahydrophone, or the like. The present invention further contemplates theuse of a plurality of leads 164 and/or agent channels 163. In oneembodiment of the present invention, agent channel 163 comprises atleast one lumen constructed from plastic, metal, rubber, or othermaterial suitable for use in surgical procedures.

FIG. 9 illustrates an embodiment of the invention that combines thedisclosures of FIGS. 1 and 5 and enables operation of a surgicalinstrument in both the KHz and MHz operating range. Shown is a sectionof elongated portion 268 of an overall system as shown in FIG. 5.Residing inside elongated portion 268 may be an agent channel 263, atransducer 265 in combination with a coaxial cable 266 for MHzoperation, a solid waveguide 246 in combination with end effector 260for KHz operation, and a lead 264. Agent channel 263 delivers the agent275 from the proximal end of coupled ultrasound instrument 250 (notshown) to the semi-permeable membrane 255. Coaxial cable 266 deliverselectrical energy to transducer 265. In one embodiment, whenelectrically activated, transducer 265 operates preferably at 0.5-50MHz. Lead 264 may be used to transmit a signal from the distal end ofcoupled ultrasound instrument 250 to generator 10 such as, for example,temperature information from a thermocouple, acoustic noise level from ahydrophone, pulse-echo information from the target region, or the like.The present invention contemplates the use of a plurality of coaxialcables 266, leads 264, and/or agent channels 263. Coaxial cable 266 maybe designed from any conductive material suitable for use in surgicalprocedures. In one embodiment of the present invention, agent channel263 comprises at least one lumen constructed from plastic, metal,rubber, or other material suitable for use in surgical procedures.

The coupled ultrasonic instrument (not shown) comprises the use of anend effector 260 (kHz operation) connected to a waveguide 246 incooperation with a transducer 265 (MHz) connected to a coaxial cable 266and a semi-permeable membrane 255 connected to agent channel 263.Waveguide 246 may be coupled to an electromechanical element (not shown)located at the proximal end of the coupled ultrasonic instrument. In oneembodiment of the present invention, the electro-mechanical elementconnected to waveguide 246 operates at 10-200 kHz. In one embodiment ofthe present invention, transducer 265 operates preferably at 0.5-50 MHz,and more preferably at 0.5-10 MHz. Accordingly, end effector 260 may beused simultaneously or alternately with transducer 265, or end effector260 and transducer 265 may be used independently. The present inventioncomprises the method of using waveguide 246 with end effector 260 and/ortransducer 265 to perform excision, hemostasis, ablation, and/orcoagulative necrosis, prior to the delivery of agent 275 tosemi-permeable membrane 255. Following necessary excision andhemostasis, agent 275 may be delivered through agent channel 263 intosemi-permeable membrane 255, or agent 275 may be delivered systemically.

When transducer 265 and/or end effector 260 are activated, agent 275 isdriven through semi-permeable membrane 255, producing agent droplets277. A suitable semi-permeable membrane 255 may be formed from, forexample, nitrocellulose, tyvek, silicone, ethelyne vinyl acetate, or thelike. Agent droplets 277 are then driven preferentially into tissue 240by ultrasound energy, as shown below in ultrasound mediated diffusionexperiment results. The coupled ultrasonic instrument further comprisesthe use of a suction system, an irrigation system, a snare, a viewingmeans, and/or a number of cutting and/or coagulation means such as, forexample, laser or electrosurgical energy. The waveguide 246 andassociated end effector 260 may be used in cooperation with transducer265 to facilitate a local (omnidirectional) tissue effect or a distant(focused) tissue effect depending on the needs of the application. Thecoupled ultrasound instrument further contemplates a transducer 265surrounded by semi-permeable membrane 255, where agent channel 263 maybe within or substantially near transducer 265 to facilitate thedelivery of agent 275 into semi-permeable membrane 255 surroundingtransducer 265. In a further embodiment of the present invention,semi-permeable membrane 255 may surround end effector 260, or maysurround both end effector 260 and transducer 265.

FIG. 10 illustrates an ultrasonic system 325 for local delivery of anagent in combination with an intense ultrasound instrument 350 foractivating or assisting transport of the agent 375 in combination with afirst feedback device 366 and a second feedback device 367. Feedbackdevices 366 and 367 may be one or a plurality of piezo sensors, piezoreceivers, thermocouples, non-thermal response monitors, thermalresponse monitors, cavitation monitors, streaming monitors, ultrasonicimaging devices, drug activation monitors, infusion rate controls,source controls, duty cycle controls, frequency controls, or othersuitable means of monitoring and/or controlling a surgical procedure.Unless otherwise specified, all “300” series reference numerals have thesame function as the corresponding reference numerals of FIG. 1, but itis evident that feedback devices 366 and 367 are useful in any of theembodiments of the invention presented herein.

In one embodiment of the present invention, first feedback device 366 isa piezo sensor attached to the distal portion of end effector 360, iscoupled via wire 370 to a feedback monitor (not shown), in the form of abroad bandwidth pulser-receiver. Feedback device 366 in the form of apiezo sensor may be driven and controlled by the broad bandwidthpulser-receiver in order to acquire standard A-line (pulse echo) datafrom the region of interest, and to monitor morphological changes in thetissue 40. A further embodiment of the present invention comprises afeedback device 366 in the form of a piezo sensor used to estimate thetemperature of the treatment volume using ultrasonic (remote) means,such as change in sound speed and/or the attenuation coefficient, and tofacilitate monitored therapy. A further embodiment of the presentinvention contemplates feedback device 366 in the form of a piezoreciever to actively, and/or passively, monitor the cavitationalactivity in the therapy zone. Used in cooperation with a broad bandwidthpulser-receiver, this technique can be implemented by recording andprocessing the broad bandwidth acoustic emissions resulting from thebubble growth and collapse due the therapeutic ultrasound field in theregion of treatment. Alternatively, the higher harmonic such as, forexample, the 2^(nd) or 3^(rd), or the sub-harmonic response due to thehigh-power field in the therapeutic zone can be recorded and correlatedto the tissue therapy, or to estimate the amount of agent 75 activated.Further, the streaming field resulting from the therapy acoustic fieldmay be monitored using Doppler flow techniques. The strength of the flowsignal may be correlated to the magnitude of advection, or delivery ofagent 75, within the treatment volume.

A second feedback device 367 may be a thermocouple attached to theelongated portion 368 comprising at least one wire 371, where at leastone wire 371 is attached to both second feedback device 367 and to afeedback monitor (not shown). Feedback monitor (not shown) may be forexample, a broad bandwidth pulser-receiver, or other suitable means ofmonitoring and/or controlling a surgical procedure. Wire 371 may beconstructed from silver, stainless steel, or other conductive materialsuitable for use in surgical procedures. Second feedback device 367 maybe located at any point along elongated portion 368 depending on theneeds of a particular medical application. In one embodiment of thepresent invention, feedback device 367 may be a thermocouple attached toelongated portion 368, where the feedback device 367, in the form of athermocouple, monitors the region of interest during ablation and/ordrug activation phases.

The present invention contemplates one or a plurality of feedbackdevices 366 and/or feedback devices 367 used within a system feedbackloop to control, for example, the therapy source, pulsing, treatmenttime, and/or rate of drug infusion, in order to optimize the ablativeand drug activation-based treatments.

Protocol for Ultrasound-Mediated Diffusion Experiments

A method for treating tissue in accordance with the present inventioncomprises the steps of: providing a surgical instrument, the instrumentcomprising: a housing; a transducer connected to the housing; asemi-permeable membrane surrounding the transducer; a pharmaceuticalagent; and an agent delivery system; inserting the surgical instrumentinto a body cavity of a patient; delivering a drug to the patient; andlocally activating the drug with the surgical instrument. For purposesherein, locally is defined as within a range of about 0.5 mm to 50 mmfrom the end-effector of the instrument. Other steps in accordance withthe present invention include achieving hemostasis, excising tissue,coagulating tissue, and cutting tissue.

Experiments were performed to determine if the present invention couldtransport a chemical agent of interest to a potential therapeutic site.An appropriate agent, Vorozole, a model chemical agent from JanssenPharmaceutica in Belgium was selected as a chemical drug for permeationthrough biological barriers.

The representative 20 kHz and 1 MHz sources are described as follows.The 20 kHz sonicator system is available from Cole Parmer, Inc., VernonHills, Ill.—Ultrasonic Homogenizer, Model CPX 400. The 1 MHz source wasa custom designed transducer available from UTX, Inc., Holmes, N.Y.(e.g., UTX Model #9908039). A suitable acoustic power output ranges from1-10 W, pulsed at 5-75% duty cycle. A suitable source geometry rangesfrom 1-5 MHz, flat geometry (19 mm diameter ceramic disks (preferablyPZT-4)). Transducers should be designed for high-power long-termoperation (up to 26 hours), air or Corporene-backed (narrow bandwidthtuning), high-temperature epoxy front face matching. Embeddedthermocouples in close proximity of the ceramic may provide feedback forthe source surface temperature. A number of source cooling schemes maybe implemented (for example, transducer housing with a water jacket, orcirculating water at the front face of transducer, separated from thedrug reservoir by using polymer-based membranes or stainless steel shimstock). The cable for the transducers may be double-shielded coax,teflon coated (high-temperature), or gold braided thin-gauge cable.

For active diffusion experiments with Vorozole, 16 ml of 5% HP-1-CD with0.05% NaN₃ in water was added into the receptor compartment of glassdiffusion cells. A Teflon-coated magnetic stirring bar was also added inthe receptor compartment. The Franz cells were then placed on top of astirring plate set at about 600 rpm.

To perform the ultrasound-mediated experiments, a 20 kHz and a 1 MHzprobe were mounted in the donor compartment close to the skin surface.The formulations were added until the probes were immersed in the liquidand ultrasound sources were turned on.

The power setting indicated on the 20 kHz system relates to acorrespondingly increased acoustic field radiated from the horn tip. Theacoustic power radiated by the MHz frequency transducers was nominally˜4 W for the voltage used in our study at 1 MHz. In addition, theacoustic intensity over time (I_(temporal)) was a function of thepulsing regime used for a given experiment.

The experiments were conducted over 20 hours. Samples were collected inthe following successive order: 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16,20 hours.

After the incubation period, the receptor fluid was collected and storedat 4° C. until HPLC analysis was performed. The formulation was removedfrom the donor side with a syringe and Kleenex tissues. The diffusioncells were dismantled and the skin was carefully removed. The surfacewas cleaned consecutively with a dry Kleenex tissue, an ethanol-wettedtissue and a dry tissue. The skin was evaluated for morphologic changesdue to the exposure to ultrasound.

Parallel experiments for passive diffusion of the drug were conductedwhereby the set-up was identical for ultrasound exposure to the tissue,except that the skin was not exposed to any ultrasound energy. Theresult of the above experiment is illustrated in FIG. 11, illustratingthat an ultrasonic surgical instrument 50 increases the transport ofVorazol through tissue. Specification A is 20 kilohertz ultrasound witha tip displacement of approximately 10 micrometers peak-to-peak, 0.5Seconds on, 12.5% duty cycle. Specification B is 1 Megaherts ultrasoundat approximately 4 Watts power, 4 seconds on at 50% duty cycle.Specification C is passive permeation.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. Accordingly, it isintended that the invention be limited only by the spirit and scope ofthe appended claims.

1. An ultrasonic surgical system comprising: a housing; a transducerconnected to said housing; a membrane surrounding said transducer; and apharmaceutical agent within the membrane; and an agent delivery system.2. The ultrasonic surgical system of claim 1, wherein said transduceroperates within the range of about 500 kilohertz to about 50 megahertz.3. The ultrasonic surgical system of claim 2, wherein said transduceroperates within the range of about 500 kilohertz to about 2 megahertz.4. The ultrasonic surgical system of claim 3, wherein said membrane isporous or semi-permeable.
 5. The ultrasonic surgical system of claim 1,further comprising a feedback device selected from the group consistingof a non-thermal response monitor, a thermal response monitor, acavitation monitor, a streaming monitor, an ultrasonic imaging device, adrug activation monitor, an infusion rate control, a source control, aduty cycle control, a piezo sensor, a piezo receiver, a thermocouple,and a frequency control.
 6. An ultrasonic instrument comprising: ahousing; a transducer connected to said housing; a membrane surroundingsaid transducer; a pharmaceutical agent; and an agent delivery system;wherein said agent delivery system delivers said pharmaceutical agentinto a chamber of said membrane; and whereby said pharmaceutical agentis driven through said membrane by ultrasonic energy delivered from saidtransducer.
 7. A method of treating tissue comprising the steps of: a)providing a surgical instrument, said instrument comprising: a housing;a transducer connected to said housing; b) inserting said surgicalinstrument into the patient; c) delivering a drug to said patient; andd) locally activating said drug with said surgical instrument.
 8. Themethod of claim 7 further comprising the step of: e) ablating tissue ofsaid patient with said surgical instrument.
 9. An ultrasonic surgicalsystem comprising: a) a generator; b) an instrument comprising: i) ahousing; ii) an electromechanical element contained in an interiorportion of said housing; iii) a waveguide originating at saidelectromechanical element and terminating at an end-effector extendingout of said housing; iv) a membrane surrounding said end-effector; v) apharmaceutical agent; and vi) an agent delivery system; wherein saidgenerator is adapted to provide electrical energy to saidelectromechanical element; wherein said transducer is adapted to convertsaid electrical energy into mechanical energy; and whereby saidpharmaceutical agent is driven through said membrane by said mechanicalenergy.
 10. The ultrasonic surgical system of claim 9, wherein saidelectromechanical element operates within the range of about 10kilohertz to about 200 kilohertz.
 11. The ultrasonic surgical system ofclaim 9, wherein said membrane is porous or semi-permeable.
 12. Anultrasonic surgical instrument comprising: a) a housing; b) a transducerconnected to said housing; c) a membrane adjacent said transducer; d) apharmaceutical agent; and e) an agent delivery system; wherein saidagent delivery system delivers said pharmaceutical agent into a chamberof said membrane.
 13. The ultrasonic surgical system of claim 12,wherein said transducer operates within the range of about 500 kilohertzto about 50 megahertz.
 14. The ultrasonic surgical system of claim 12,wherein said transducer operates within the range of about 10 kilohertzto about 200 kilohertz.
 15. The ultrasonic surgical system of claim 12,wherein said membrane is porous or semi-permeable.